Abstract
The importance of insulin-like growth factor I (IGF-I) on maintenance of skeletal integrity has been widely recognized. Although osteoblasts secrete some IGF-I, the liver is the primary endocrine source for IGF-I. We have studied the regulation of the human IGF-I promoter in the hepatocyte cell line Hep3B, and we have shown that the IGF-I promoter, when co-transfected in Hep3B cells together with an estrogen receptor (ER)-alpha expression vector, was transcriptionally regulated by raloxifene or raloxifene-like molecules but not by 17beta-estradiol and 4(OH)-tamoxifen. The induction mediated by raloxifene is antagonized by 17beta-estradiol and mediated selectively by ER-alpha, but not by ER-beta. Transfer of IGF-I promoter sequences from -733 to -65 or from -375 to -65 to a minimal Fos promoter resulted in a comparable responsiveness to raloxifene. This region contains two CAAT/enhancer-binding protein sites and an activator protein 1 site, both of which have been shown to be involved in estrogen receptor-mediated transactivation. When the CAAT/enhancer-binding protein sites were mutated in a construct bearing the sequence from -375 to -65 in front of the minimal Fos promoter, raloxifene induction was reduced, whereas mutation of the other elements did not affect induction. In addition, using chimeric proteins, we delineated the domains of ER-alpha that confer to ER-alpha transactivation abilities on the IGF-I promoter that are not exhibited by ER-beta. These data shed new light on the mechanism of action of antiestrogens and might help explain, at least in part, the bone-protective effects observed for some antiestrogens in ovariectomized animals.
Highlights
IGF-I1 is a pleiotropic hormone involved in several aspects of growth and development, and it plays an important role in maintaining bone mass [1]
We have studied the regulation of the human insulin-like growth factor I (IGF-I) promoter in the hepatocyte cell line Hep3B, and we have shown that the IGF-I promoter, when co-transfected in Hep3B cells together with an estrogen receptor (ER)-␣ expression vector, was transcriptionally regulated by raloxifene or raloxifene-like molecules but not by 17estradiol and 4(OH)-tamoxifen
The IGF-I Promoter Is Regulated in an ER-␣-dependent Manner by Several Antiestrogens, but not by 17-Estradiol—We compared the effects of estrogen and antiestrogens on the regulation of the human IGF-I gene
Summary
IGF-I1 is a pleiotropic hormone involved in several aspects of growth and development, and it plays an important role in maintaining bone mass [1]. The dramatic decrease in circulating estrogen occurring at menopause might play a central role in the decrease of this local skeletal IGF-I production This continuous decline in IGF-I activity with age may be a major cause of bone loss [8]. Three distinct classes of antiestrogens have been described, ranging from pure antagonists such as ICI 182,780 to partial agonists such as tamoxifen and raloxifene, which exert tissue-selective estrogen-like effects [10]. Because of the potential impact of liver IGF-I production on bone and more generally on the aging process [6, 7, 8], we studied the effects of estrogen and antiestrogens on transcription of the human IGF-I gene. We found that two C/EBP sites are necessary for this ER-␣mediated induction of the IGF-I promoter
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